KiDNEY DISEASE IN MULTIPLE MYELOMA

1. KiDNEY DISEASE IN MULTIPLE MYELOMA Elizabeth Dehmer AM Report 9/3/2008

2. Multiple Myeloma Clonal proliferation of malignant plasma cells in bones and bone marrow, resulting in bone pain, pathologic fractures, bone marrow failure, metabolic and renal dysfunction 1% of malignancies 10% of hematologic malignancies African Americans 2x incidence of Caucasians Males > females Median age at diagnosis is older than 65 yrs Pts with Cr < 1.5 have 1 yr survival rate of 80%, Cr > 2.3 have 50% 1 yr survival rate

3. Types of kidney disease And prevalence in multiple myeloma Myeloma cast nephropathy 30-50% (Myeloma Kidney) Intersitial nephritis/fibrosis 20-30% without cast nephropathy Amyloidosis 10% Light-chain deposition disease 5% Acute tubular necrosis 10% Other (urate nephropathy, tubular 5% crystals, hypercalcemia, focal segmental glomerulosclerosis) ++

4. MYELOMA kidney An excess of filtered monoclonal light chains are transported to the interstitium of the kidney via specific receptors in the proximal tubule. The receptors become overloaded by light chains, which combine with Tamm-Horsfall protein, forming obstructive casts in the renal tubules. In 30% of cases of renal impairment, the biopsy does NOT show extensive cast formation despite development of interstitial tubular injury and fibrosis. Prolonged exposure to nephrotoxic light chains can therefore be associated w/ intense intersitial inflammation, fibrosis and tubular atrophy as hallmark of renal injury.In 30% of cases of renal impairment, the biopsy does NOT show extensive cast formation despite development of interstitial tubular injury and fibrosis. Prolonged exposure to nephrotoxic light chains can therefore be associated w/ intense intersitial inflammation, fibrosis and tubular atrophy as hallmark of renal injury.

5. Myeloma kidney:Clinical presentation Constitutional symptoms such as fatigue, weight loss Skeletal pain, lytic bone lesions Normal-sized kidneys, bland urine (hematuria is rare), proteinuria < 3 g/l Anemia very common, less common are thrombocytopenia or leukopenia Hypercalcemia or normal corrected calcium

6. Myeloma kidney:diagnosis Order “Myeloma workup, urine” for UPEP and urine immunofixation (looking for monoclonal protein) Order “Myeloma workup, serum” to get SPEP, IgG, IgA, IgM, serum immunofixation (looking for monoclonal protein) Order “serum light chains, quant” to get serum kappa and lambda free light chains Provides the kappa/lambda free light chains ratio Normal range 0.26-1.65 ?:? If < 0.26, oversecretion of lambda If > 1.65, oversecretion of kappa May need bone marrow or renal biopsy

7. Myeloma Kidney:Treatment Consider plasma exchange to reduce light chain load (controversial) High dose dexamethasone (40 mg daily) can reduce light chain load Manage contributing factors to renal impairment: treat hypercalcemia, sepsis; keep patient hydrated; avoid NSAIDS and contrast agents Treat underlying disease: chemotherapy, autologous stem cell transplantation Patients may require renal replacement therapy Solubility of light chains adversely affected by reductions in GFR-?KEEP HYDRATED-volume expansion to increase GFR can decrease single nephron LC concentration and increase tubular flow. No evidence for sodium bicarb though acidic urine favors cast formation, consider esp if metabolic acidosis but KEEP PT HYDRATED whether NaCl or Na bicarb Avoid diuretics-Lasix-may favor cast formation Melphalan and prednisone 4 day infusion of adriamycin + vincristine plus high dose dexamethasone, VAD (vincristine, doxorubicin, dexamethasone), cyclophosphamide/dexamethasone, velcade (bortezomib/dexamethasone)Solubility of light chains adversely affected by reductions in GFR-?KEEP HYDRATED-volume expansion to increase GFR can decrease single nephron LC concentration and increase tubular flow. No evidence for sodium bicarb though acidic urine favors cast formation, consider esp if metabolic acidosis but KEEP PT HYDRATED whether NaCl or Na bicarb Avoid diuretics-Lasix-may favor cast formation Melphalan and prednisone 4 day infusion of adriamycin + vincristine plus high dose dexamethasone, VAD (vincristine, doxorubicin, dexamethasone), cyclophosphamide/dexamethasone, velcade (bortezomib/dexamethasone)

8. AL Amyloidosis Monoclonal plasma cell dyscrasia in which secreted immunoglobulin is deposited as fibrils in kidneys, heart, peripheral nerves Overrepresentation of lambda light chains Incidence is 9 per million per year; fewer than 1 in 4 is considered to have an overt immunoproliferative disease (multiple myeloma, Waldenstrom’s macroglobulinemia)

9. AL amyloidosis:clinical presentation Constitutional: weakness, weight loss Renal: nephrotic syndrome, renal insufficiency w/ marked kidney enlargement usually without hypertension, RTA, polyuria, polydipsia, no hematuria Cardiac: restrictive cardiomyopathy, arrhythmias, sick sinus syndrome, angina, MI GI: motility disturbances, malabsorption, hemorrhage, obstruction, macroglossia, Neuro: peripheral neuropathy, autonomic neuropathy w/ severe orthostatic hypotension Skin: purpura, ecchymoses, papules, nodules, plaques-usually on face and upper trunk Rheum: can mimic RA Heme: acquired bleeding diathesis

10. Al amyloidosis:Diagnosis Immunofixation of serum and urine to demonstrate monoclonal light chain (2:1 ?:?) Bone marrow specimen Histologic diagnosis: try least invasive alternatives first (salivary glands, subcutaneous fat pad, rectal biopsy) but may require organ biopsy

11. AL Amyloidosis:pathology Amyloid deposits are noted in the H&E stained ( 400) glomeruli (a), and confirmed with Congo Red staining (b) exhibiting a salmon pink appearance. A macrophage type of mesangial cell is noted associated with numerous fibrils with characteristics of amyloid ( 22 500) (c) and LCs are highlighted by immunogold labeling (d) using 20 nm gold particles ( 35 000).Amyloid deposits are noted in the H&E stained ( 400) glomeruli (a), and confirmed with Congo Red staining (b) exhibiting a salmon pink appearance. A macrophage type of mesangial cell is noted associated with numerous fibrils with characteristics of amyloid ( 22 500) (c) and LCs are highlighted by immunogold labeling (d) using 20 nm gold particles ( 35 000).

12. AL amyloidosis:treatment + prognosis Chemotherapy Conventional: low-dose melphalan + prednisone High dose melphalan + peripheral blood stem cell transplantation Patients may require renal replacement therapy, however this may by complicated by hypotension, GI hemorrhage, chronic diarrhea, difficulties w/ vascular access Median survival 10 months 40% of deaths due to CHF/arrhythmias

13. Light chain deposition disease Glomerular deposits of nonfibrillar material, which is Congo red negative. Now often called monoclonal immunoglobulin deposition disease b/c in some patients, deposits may be composed of heavy chain fragments. Light chain is generally of kappa type Occurs in a wide range of ages-28 to 94 years Males > females Myeloma diagnosed in 50% of patients

14. Light chain deposition disease:clinical presentation Renal: proteinuria (often nephrotic range), hematuria, prevalence of hypertension is variable. High prevalence, early appearance, and severity of renal failure are all features of LCDD Extrarenal: Liver and cardiac manifestations are most common, including hepatomegaly, elevated LFTs, cardiomegaly, CHF, arrhythmias. Others include peripheral neuropathy, GI disturbance, pulmonary nodules, arthropathy, sicca syndrome.

15. Light chain deposition disease:diagnosis SPEP, UPEP, urine immunofixation, serum immunofixation, serum free light chains These techniques can fail to identify a monoclonal immunoglobulin in 10-20% of pts Therefore, renal biopsy essential! Also need bone marrow aspiration and biopsy to diagnose plasma cell dyscrasia

16. Light Chain Deposition Disease:Pathology Nodular sclerosis (left), thickening of basement membranes (right). Interstitial fibrosis is also a constant findingNodular sclerosis (left), thickening of basement membranes (right). Interstitial fibrosis is also a constant finding

17. Light Chain Deposition disease:Pathology Immunoflourescence shows kappa light chain fixation along tubular basement membranesImmunoflourescence shows kappa light chain fixation along tubular basement membranes

18. Light chain deposition disease:treatment + prognosis Chemotherapy Bone marrow transplant Survival varies from 1 month to 10 years Age, initial creatinine level, associated multiple myeloma and extra-renal light chain deposition independently associated w/ worse survival Patients may need renal replacement therapy Recurrence of disease seen in kidney transplant patients

19. USC #1

20. References Feehally, John, Jurgen Floege and Richard Johnson. Comprehensive Clinical Nephrology 3rd Ed. Philadelphia: Mosby Elsevier, 2007. Blade, Joan and Laura Rosinol. Complications of Multiple Myeloma. Hematology/Oncology Clinics of North America 2007;21:1231-46. Penfield JG. Multiple Myeloma in ESRD. Seminars in Dialysis 2006;19:329-34.

21. References Types of kidney disease in multiple myeloma. Uptodate online Multiple Myeloma. MKSAP Hematology and Oncology. AL Amyloidosis. MKSAP Hematology and Oncology. Multiple Myeloma. MKSAP Nephrology.